Small Business Assistance: Frequently Asked Questions on the Regulatory Process of Over-the-Counter (OTC) Drugs

Introduction

1. What is an Over-the-Counter (OTC) Drug Product?

An OTC drug product is a drug product marketed for use by the consumer without the intervention of a health care professional in order to obtain the product. Two post-1938 regulatory pathways exist for the legal marketing of such products:

marketing in compliance with an OTC drug monograph

marketing under the authority of an approved product-specific new drug application (NDA), or an abbreviated new drug application (ANDA)

2. What is a prescription drug product?

A prescription drug product is a drug product approved for marketing that can only be obtained with a prescription from an appropriate health care practitioner.

3. What is the OTC drug review?

The OTC drug review was established to evaluate the safety and effectiveness of OTC drug products marketed in the United States before May 11, 1972. It is a three-phase public rulemaking process (each phase requiring a Federal Register publication) resulting in the establishment of standards (monographs or non-monographs) for an OTC therapeutic drug category.

The first phase was accomplished by advisory review panels. The panels were charged with reviewing the ingredients in nonprescription drug products to determine whether these ingredients could be generally recognized as safe and effective for use in self-treatment. They were also charged with reviewing claims and recommending appropriate labeling, including therapeutic indications, dosage instructions, and warnings about side effects and preventing misuse.

According to the terms of the review, the panels classified ingredients in three categories as follows:

Category I: generally recognized as safe and effective for the claimed therapeutic indication;

Category II: not generally recognized as safe and effective or unacceptable indications;

Category III: insufficient data available to permit final classification

5. What is the second phase of the OTC drug review?

The second phase of the OTC drug review was the agency’s review of ingredients in each class of drugs, based on the panel’s findings, on public comment, and on new data that may have become available. The agency, in turn, publishes its conclusions in the Federal Register in the form of a tentative final monograph. After publication of the tentative final monograph, a period of time is allotted for objections to the agency’s proposal or for requests to be submitted for a hearing before the Commissioner of FDA.

6.What is the third phase of the OTC drug review?

The publication of final regulations in the form of drug monographs is the third and last phase of the review process. The monographs establish conditions under which certain OTC drug products are generally recognized as safe and effective.

approval of a new drug submitted under section 505(b)(2) of the FD&C Act

approval of an abbreviated new drug application under section 505(j) of the FD&C Act

licensure of certain biological products under section 351 of the Public Health Service Act

8. What is a 505(b)(1) application?

A 505(b)(1) application is an application that contains full reports of investigations of safety and effectiveness.

The investigations the applicant relied on for approval were conducted by, or for the applicant, or the applicant has obtained a right of reference or use for the investigations.

9. What is a 505(b)(2) application?

A 505(b)(2) application is one described under section 505(b)(2) of the FD&C Act as an application for which one or more of the investigations relied upon by the applicant for approval "were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted" (21 U.S.C. 355(b)(2)). This provision permits FDA to rely on a previous finding of safety and effectiveness that led to approval of an NDA or on data not developed by the applicant such as published literature.

505(b)(2) applications are submitted under section 505(b) of the Act and are therefore subject to the same statutory provisions that govern 505(b)(1) applications that require among other things, "full reports" of safety and effectiveness.

10. What is an Abbreviated New Drug Application (505)(j)?

An abbreviated new drug application is described under section 505(j) of the Act as an application that contains information to show that the proposed product is identical in active ingredient, dosage form, strength, route of administration, labeling, quality, performance characteristics and intended use, among other things to a previously approved application (the reference listed drug (RLD)). ANDAs do not contain clinical studies as required in NDAs but are required to contain information establishing bioequivalence to the RLD. In general, the bioequivalence determination allows the ANDA to rely on the agency’s finding of safety and efficacy for the RLD.

11. What is a supplement to an approved application?

The Federal Food, Drug, and Cosmetic Act says, “The term supplement means a request to the Secretary to approve a change in a human drug application which has been approved.” Each indication or claim is considered a separate change for which a separate supplement should be submitted. This policy allows FDA to approve each indication or claim when it is ready for approval rather than delaying approval until the last of a group of indications or claims is ready to be approved.

The OTC monographs represent regulatory standards for the marketing of non-prescription drug products not covered by new drug applications. These standards provide the marketing conditions for some OTC drug products including the active ingredients, labeling, and other general requirements.

13. Is pre-clearance necessary if the standards of the OTC monograph are met?

No. Marketing pre-clearance of OTC drug products by the FDA is not required if the standards of the applicable monograph are met. Additional requirements for the marketing of human drug products may be found in Title 21 of the Code of Federal Regulations containing parts 200-299 and 300-499.

14. Are there other options for marketing an OTC drug products besides on OTC monograph?

Yes. A 505(b)(1) application, a 505(b)2 application, or an abbreviated new drug application can be submitted.

15. What is the appropriate process to request amendment or repeal of conditions covered by exiting proposed or final OTC monographs?

An NDA can be used to request approval of an OTC drug that deviates in any respect from a monograph that has become final (see 21CFR 330.11).

However, a citizen petition (see 21 CFR 10.30) is another means to request an amendment or repeal of conditions covered by an existing proposed or final OTC drug monograph. In order for FDA to act on the petition, accompanying data must demonstrate general safety and effectiveness (or lack thereof). An advantage of submitting a citizen petition is that a Prescription Drug User Fee Act (PDUFA) fee is not required as with a NDA. But the NDA process does provide confidentiality during the review, an established review timeframe (as provided under PDUFA), and a period of potential marketing exclusivity upon approval, if certain conditions are met.

Prescription to OTC switch refers to over-the-counter marketing of a product that was once a prescription drug product, for the same dosage form, population, and route of administration.

17. How is a prescription to OTC switch accomplished?

An efficacy supplement should be submitted to an approved NDA for a prescription product if the sponsor plans to switch the drug product covered under the NDA to OTC marketing status in its entirety without a change in the previously approved dosage form or route of administration. An NDA 505(b)(1) should be submitted if the sponsor is proposing to convert some but not all of the approved prescription indications to OTC marketing status. An original NDA (505)(b)(1) or 505(b)(2) needs to be submitted if the sponsor plans to market either a new product OTC whose active substance, indication, or dosage form has never previously been marketed OTC.

Time and Extent Application

18. What is the purpose of a time and extent application?

The purpose of a Time and Extent Application (TEA) is to request that applicable conditions be considered for inclusion in the OTC monograph system (21 CFR 330.14). Submission of a TEA is only the first step of a two-step process to demonstrate eligibility of the condition for the OTC monograph review process. A TEA should only be submitted for conditions that the applicant believes have been marketed over-the-counter to “a material extent” and “for a material time” as follows:

Those initially marketed under a NDA in the U.S. after the OTC drug review began in 1972.

Those without any U.S. marketing experience.

Those not generally recognized as safe and effective (i.e., “non-monographs”) in the original OTC drug review but for which additional data and information are being presented. The condition(s) must have been marketed for over-the-counter purchase by consumers and for at least five continuous years in the same country in sufficient quantity (more than one country may be necessary depending on the extent of marketing).

If FDA believes that material time and extent has been demonstrated through the TEA, the condition is then declared eligible for the monograph review. The second step of the process, requiring demonstration of general safety and effectiveness, follows.

19. What is a "condition" for an OTC drug product?

Condition refers to an active ingredient or botanical drug substance (or combination of both), dosage form, dosage strength, or route of administration marketed for a specific over-the-counter use. This includes conditions regulated as cosmetic products or dietary supplements in a foreign country(ies) that would be regulated as OTC drugs in the United States.

20. Where can I find additional information on the time and extent application?

In the Federal Register of March 17, 1999 (PDF - 1MB), FDA published a final regulation (21 CFR 201.66), establishing standardized content and format for the labeling of OTC drug products. Standardized labeling for OTC drug products is intended to make it easier for consumers to read and understand OTC drug products safely and effectively. The labeling regulations in 21 CFR 201.66 cover all OTC drug and drug-cosmetic products,whether marketed under a 505(b)(1) application, a 505(b)(2) application, abbreviated new drug application ,or an OTC drug monograph.

Professional Labeling

22. What is professional labeling?

Some OTC monographs contain professional labeling that provides specific information to health professionals for uses not included in OTC drug labeling.

23. What monographs contain professional labeling?

otc drug monographs with professional labeling include those in the following drug categories: